chr11-68312746-C-CGCTGCT
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_002335.4(LRP5):c.55_60dupCTGCTG(p.Leu19_Leu20dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,061,312 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002335.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRP5 | ENST00000294304.12 | c.55_60dupCTGCTG | p.Leu19_Leu20dup | conservative_inframe_insertion | Exon 1 of 23 | 1 | NM_002335.4 | ENSP00000294304.6 | ||
LRP5 | ENST00000529993.5 | n.55_60dupCTGCTG | non_coding_transcript_exon_variant | Exon 1 of 23 | 1 | ENSP00000436652.1 |
Frequencies
GnomAD3 genomes AF: 0.00126 AC: 182AN: 144330Hom.: 1 Cov.: 28
GnomAD3 exomes AF: 0.000491 AC: 8AN: 16308Hom.: 0 AF XY: 0.000507 AC XY: 5AN XY: 9856
GnomAD4 exome AF: 0.000878 AC: 805AN: 916896Hom.: 2 Cov.: 5 AF XY: 0.000892 AC XY: 391AN XY: 438478
GnomAD4 genome AF: 0.00125 AC: 181AN: 144416Hom.: 1 Cov.: 28 AF XY: 0.00125 AC XY: 88AN XY: 70312
ClinVar
Submissions by phenotype
not provided Uncertain:2
Previously reported in German and Turkish control individuals, with a frequency of less than 1%, as compared to 90% frequency of the wild type LRP5 variant with 9 Leucine repeats (PMID: 19177549); Published functional studies expressed human LRP5 with different Leucine repeats number (3-Leu to 11-Leu) of signal peptide in HEK293 cells; Luciferase assay showed ~40% reductions in activity of LRP5 with 11-Leu compared to the wild type (9-Leu); Western blot assay showed that 11-Leu LRP5 had greater retention in the cytoplasmic fraction compared to the wild type (PMID: 19177549); In-frame duplication of two Leucine amino acids in the signal peptide sequence of LRP5, leading to 11 Leucine repeats; wild-type sequence has 9 Leucine repeats; In-frame duplication of 2 amino acids; This variant is associated with the following publications: (PMID: 32483926, 34860240, 19177549) -
This variant, c.55_60dup, results in the insertion of 2 amino acid(s) of the LRP5 protein (p.Leu19_Leu20dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with LRP5-related conditions (PMID: 32483926, 34860240). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LRP5 function (PMID: 19177549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
The c.55_60dupCTGCTG (p.L19_L20dup) alteration is located in exon 1 (coding exon 1) of the LRP5 gene. The alteration consists of an in-frame duplication of 6 nucleotides from position 55 to 60, resulting in the duplication of 2 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Retinal dystrophy Uncertain:1
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not specified Benign:1
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Osteogenesis imperfecta Benign:1
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LRP5-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at